Macrophage-CITED2 and inflammatory gene expression

CITED2 is a member of the CBP/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain family of transcriptional regulators and is exclusively localized in the nucleus. Previous studies have demonstrated that CITED2 plays an important role in cellular development and differentiation. Experimental murine studies have shown that Cited2 mutation or deficiency results in congenital heart and neural crest defects, impairment in the development of lung, liver, placenta, and adrenal tissue, and perturbation in the left-right patterning of the body axis. Previous studies have also show that CITED2 is predominantly expressed in murine and human macrophages. Myeloid-specific CITED2 deficient mice are highly susceptible to lipopolysaccharide (LPS)-induced endotoxic shock syndrome, zymosan-induced lung inflammation, and experimental atherogenesis. Mechanistically, CITED2 in cooperation with PPAR? promotes anti-inflammatory gene expression while suppressing NF?B, HIF1a, STAT1, and IRF1 signaling to attenuate pro-inflammatory gene expression in macrophages. Overall design: The bone marrow derived macrophges were obtained from Lyz2cre and Lyz2cre:CITED2Fl/Fl mice (n=3). Total RNA samples derived from these BMDMs were subjected to RNAseq analyses.

CITED2属于携带富谷氨酸/天冬氨酸羧基末端结构域且可与CBP/p300相互作用的转录调节因子家族成员，且仅定位于细胞核。既往研究证实，CITED2在细胞发育与分化过程中发挥关键作用。小鼠实验研究显示，Cited2突变或缺失可导致先天性心脏与神经嵴缺陷、肺、肝、胎盘及肾上腺组织发育受损，以及躯体轴线左右模式形成紊乱。既往研究还发现，CITED2主要在小鼠和人类巨噬细胞中表达。髓系特异性CITED2缺失小鼠对脂多糖（lipopolysaccharide, LPS）诱导的内毒素休克综合征、酵母多糖诱导的肺部炎症及实验性动脉粥样硬化均具有高度易感性。从机制层面而言，CITED2可与过氧化物酶体增殖物激活受体γ（PPARγ）协同促进抗炎基因表达，同时抑制核因子κB（NF-κB）、缺氧诱导因子1α（HIF1α）、信号转导与转录激活因子1（STAT1）及干扰素调节因子1（IRF1）的信号通路，从而减弱巨噬细胞中的促炎基因表达。实验设计：从Lyz2cre及Lyz2cre:CITED2Fl/Fl小鼠中各获取3例骨髓来源巨噬细胞，提取上述骨髓来源巨噬细胞的总RNA并进行RNA测序（RNAseq）分析。